TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is correlated with poor prognosis, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody. Problems of drug resistance hinder the use of monoclonal antibodies. Subsequently, tyrosine kinase inhibitors (TKIs) have been noticed, TKIs have the advantages of multi-targets and reduced drug resistance. However, TKIs that target HER family proteins often cause adverse effects such as liver damage and diarrhea. Thus, TKIs with high selectivity are being developed. TH-4000, a prodrug that generated an active form TH-4000Effector (TH-4000E) under hypoxic condition, was evaluated in this research. We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2+ breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. TH-4000E activated Caspase-3 and induced apoptosis through a reactive oxygen species (ROS)-dependent pathway. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2+ breast cancer.

GATA3 mediates doxorubicin resistance by inhibiting CYB5R2-catalyzed iron reduction in breast cancer cells.

AIMS: Neoadjuvant chemotherapy (NAC) is the primary preoperative therapy for breast cancer. The luminal subtype of breast cancer shows less NAC response than the basal subtype, with an inefficient NAC treatment effect. Understanding of the molecular and cellular mechanisms responsible for this chemoresistance is an important issue when determining optimal treatment. METHODS: Doxorubicin-induced apoptosis and ferroptosis was investigated using cytotoxicity, western blotting, and flow cytometry assays. The role of GATA3 in modulating doxorubicin-induced cell death was investigated both in vitro and in vivo. RNA-seq, qPCR, ChIP, and luciferase assay and association analyses were performed to investigate the regulation of CYB5R2 by GATA3. The function of GATA3 and CYB5R2 in regulating doxorubicin-induced ferroptosis was evaluated with iron, ROS, and lipid peroxidation detection assays. Immunohistochemistry was performed for results validation. RESULTS: Doxorubicin-induced basal breast cancer cell death is dependent on iron-mediated ferroptosis. Overexpression of the luminal signature transcriptional factor GATA3 mediates doxorubicin resistance. GATA3 promotes cell viability by decreasing ferroptosis-related gene CYB5R2 expression and by maintaining iron homeostasis. Analyzing data from the public and our cohorts demonstrates that GATA3 and CYB5R2 are associated with NAC response. CONCLUSIONS: GATA3 promotes doxorubicin resistance by inhibiting CYB5R2-mediated iron metabolism and ferroptosis. Therefore, patients with breast cancer who display high GATA3 expression do not benefit from doxorubicin-based NAC regimens.

Integrative analyses of scRNA-seq and scATAC-seq reveal CXCL14 as a key regulator of lymph node metastasis in breast cancer.

The potentially different genetics and epigenetics in the primary tumors and metastases affect the efficacy of treatment in breast cancer patients. Nevertheless, the cellular and molecular mechanisms of breast cancer lymph node metastasis still remain elusive. Here, we employed single-cell RNA sequencing to acquire the transcriptomic profiles of individual cells from primary tumors, negative lymph nodes (NLs) and positive lymph nodes (PLs). We also performed a single-cell assay for transposase-accessible chromatin (ATAC) sequencing (scATAC-seq) of the positive and NL samples to get the chromatin accessibility profile. We identified a novel cell subpopulation with an abnormally high expression level of CXCL14 in the PL of breast cancer patients. Cell trajectory analysis also revealed that CXCL14 was increased expressed in the late pseudo-time. Moreover, based on a tissue microarray of 55 patients and the Oncomine database, we validated that CXCL14 expression was significantly higher in breast cancer patients with lymph node metastasis. Furthermore, scATAC-seq identified several transcription factors that may be potential regulation factors for the lymph node metastasis of breast cancer. Thus, our findings will improve our current understanding of the mechanism for lymph node metastasis, and they are potentially valuable in providing novel prognosis markers for the lymphatic metastasis of breast cancer.

Tumor-derived small extracellular vesicles promote breast cancer progression by upregulating PD-L1 expression in macrophages.

BACKGROUND: The metastasis of breast cancer (BC) is a complex multi-step pathological process, strictly dependent on the intrinsic characteristics of BC cells and promoted by a predisposing microenvironment. Although immunotherapy has made important progress in metastasis BC, the heterogeneity of PD-L1 in tumor associated macrophages (TAMs) in BC and the underlying mechanisms in the metastasis development of BC are still not completely elucidated. Small extracellular vesicles (sEVs) represent essential interaction mediators between BC cells and TAMs. It is worth noting to explore the underlying mechanisms typical of sEVs and their role in the metastasis development of BC. METHODS: The structure of sEVs was identified by TEM, while the particle size and amounts of sEVs were detected by BCA and NTA analysis. The specific PD-L1 + CD163 + TAM subpopulation in metastasis BC was identified by scRNA-seq data of GEO datasets and verified by IHC and IF. The function of TAMs and sEVs in metastasis BC was explored by RT-qPCR, WB, IF, flow cytometry and in vivo experiment. The expression profiles of plasma sEVs-miRNA in relation to BC metastasis was analyzed using next-generation sequencing. Further detailed mechanisms of sEVs in the metastasis development of BC were explored by bioinformatics analysis, RT-qPCR, WB and luciferase reporter assay. RESULTS: In this study, we identified that the immunosuppressive molecule PD-L1 was more abundant in TAMs than in BC cells, and a specific PD-L1 + CD163 + TAM subpopulation was found to be associated with metastasis BC. Additionally, we found that BC cells-derived sEVs can upregulate the PD-L1 expression and induce the M2 polarization, enhancing the metastasis development both in vitro and in vivo. Also, Clinical data showed that sEV-miR-106b-5p and sEV-miR-18a-5p was in relation to BC metastasis development and poor prognosis of BC patients. Further mechanistic experiments revealed that BC-derived sEV-miR-106b-5p and sEV-miR-18a-5p could synergistically promoted the PD-L1 expression in M2 TAMs by modulating the PTEN/AKT and PIAS3/STAT3 pathways, resulting in the enhancement of the BC cells invasion and metastasis. CONCLUSIONS: Our study demonstrated that BC-derived sEVs can induce metastasis in BC through miR-106b-5p/PTEN/AKT/PD-L1 and miR-18a-5p/PIAS3/STAT3/PD-L1 pathways in TAMs. Therefore, the inhibition of these specific interactions of signaling pathways would represent a promising target for future therapeutic strategies for treatment of BC.

Identification of Key Biomarkers and Candidate Molecules in Non-Small-Cell Lung Cancer by Integrated Bioinformatics Analysis.

Background: Non-small cell lung cancer (NSCLC) is the most prevalent malignant tumor of the lung cancer, for which the molecular mechanisms remain unknown. In this study, we identified novel biomarkers associated with the pathogenesis of NSCLC aiming to provide new diagnostic and therapeutic approaches for NSCLC by bioinformatics analysis. Methods: From the Gene Expression Omnibus database, GSE118370 and GSE10072 microarray datasets were obtained. Identifying the differentially expressed genes (DEGs) between lung adenocarcinoma and normal samples was done. By using bioinformatics tools, a protein-protein interaction (PPI) network was constructed, modules were analyzed, and enrichment analyses were performed. The expression and prognostic values of 14 hub genes were validated by the GEPIA database, and the correlation between hub genes and survival in lung adenocarcinoma was assessed by UALCAN, cBioPortal, String and Cytoscape, and Timer tools. Results: We found three genes (PIK3R1, SPP1, and PECAM1) that have a clear correlation with OS in the lung adenocarcinoma patient. It has been found that lung adenocarcinoma exhibits high expression of SPP1 and that this has been associated with poor prognosis, while low expression of PECAM1 and PIK3R1 is associated with poor prognosis (P < 0.05). We also found that the expression of SPP1 was associated with miR-146a-5p, while the high expression of miR-146a-5p was related to good prognosis (P < 0.05). On the contrary, the lower miR-21-5p on upstream of PIK3R1 is associated with a higher surviving rate in cancer patients (P < 0.05). Finally, we found that the immune checkpoint genes CD274(PD-L1) and PDCD1LG2(PD-1) were also related to SPP1 in lung adenocarcinoma. Conclusions: The results indicated that SPP1 is a cancer promoter (oncogene), while PECAM1 and PIK3R1 are cancer suppressor genes. These genes take part in the regulation of biological activities in lung adenocarcinoma, which provides a basis for improving detection and immunotherapeutic targets for lung adenocarcinoma.

CBX3 promotes breast cancer progression and high level of CBX3 predicts poor prognosis in patients.

Breast cancer is one of the leading cancer deaths around the world. Targeted drugs have greatly increased the survival rate of breast cancer patients in recent years. But in some patients, the current regimen is still ineffective. Therefore, more therapeutic targets for treating breast cancer are demanding. The core heterochromatin-related genes of breast cancer were identified by utilizing prognostic survival analysis and multivariate Cox hazard proportional regression analysis. Both breast cancer and adjacent normal tissue were collected and analyzed with western blot and immunohistochemistry. Colony formation assay, CCK-8 assay, and EdU assay were used to measure the effect of CBX3 on breast cancer cell growth, wound-healing assay and Transwell assay were used to analyze the effect of CBX3 on breast cancer cell migration and invasion. Flow cytometry assay and western blot were used to study the molecular mechanism of CBX3 in breast cancer. High expression of heterochromatin-related proteins CBX3, H2AFY, and SULF1 showed a poor prognosis in patients in both TCGA dataset and GEO datasets. Western blot demonstrated that the expression level of CBX3 was significantly higher in breast cancer than that in adjacent normal tissues. Colony formation assay, CCK-8 assay, and EdU assay showed that the knockdown of CBX3 could significantly inhibit breast cancer cell growth, and the overexpression of CBX3 could promote the growth of breast cancer cells. Transwell assay and wound healing assay showed that knockdown of CBX3 inhibited breast cancer cell migration and invasion, and the overexpression of CBX3 promoted breast cancer cell migration and invasion. Western blot showed that CBX3 might promote breast cancer cell proliferation, invasion, and migration in breast cancer by modulating the ERK1/2 signaling pathway and epithelial-mesenchymal transition (EMT)-related genes. CBX3 was a biomarker of poor prognosis in breast cancer patients. CBX3 promoted the proliferation of breast cancer cells through the ERK signaling pathway, and migration and invasion of breast cancer cells through EMT-related genes. The CBX3/p-ERK1/2 signaling axis might provide a new therapeutic method against breast cancer.

PHF20 is a Novel Prognostic Biomarker and Correlated with Immune Status in Breast Cancer.

Increasing evidence has demonstrated that enhanced PHF20 expression plays a crucial role in cancer development and progression. However, little is known about the prognostic value of PHF20 expression in breast cancer (BRCA). In this study, we attempted to explore the expression pattern of PHF20 and its associations with prognosis and immune status in BRCA. The gene expression data and clinical information of 1109 BRCA samples were downloaded from TCGA database. The expression level of PHF20 protein was determined using UALCAN and HPA database. Kaplan-Meier method and CIBERSORT algorithm were used to analyze the associations of PHF20 expression with overall survival (OS) and immune microenvironment, respectively. Besides, GSEA analysis was conducted to explore potential biological functions and molecular mechanisms of PHF20 in BRCA. Moreover, starBase database was applied to construct a ceRNA nework. PHF20 was highly expressed in BRCA samples both at the transcriptional and protein level, and was strongly correlated with the OS and immune status. Univariable and multivariate Cox regression analyses identified PHF20 as an independent prognostic factor. Additionally, GSEA analysis showed that high PHF20 expression was closely associated with TGF-ß signaling pathway, Wnt signaling pathway, and adherens junction. Furthermore, three ceRNA networks (AC037198.1/hsa-miR-223-3p/PHF20, CBR3-AS1/hsa-miR-223-3p/PHF20, and ZNF561-AS1/hsa-miR-223-3p/PHF20) were identified by starBase analysis. Functional experiments validated that PHF20 knockdown inhibited the cell viability and progression in BRCA cells. PHF20 overexpression was significantly associated with poor prognosis and immune status in BRCA, and could act as a potential novel prognostic biomarker for BRCA.

Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial.

BACKGROUND: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. METHODS: In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. RESULTS: Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. CONCLUSIONS: The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03588091.

M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring αM ß2 Integrin to Tumor Cells.

BACKGROUND AND AIMS: The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. APPROACH AND RESULTS: The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, αM ß2 (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. CONCLUSIONS: Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Potential values of circulating tumor cell for detection of recurrence in patients of thyroid cancer: a diagnostic meta-analysis.

BACKGROUND: Several studies have reported that circulating tumor cells (CTCs) are a promising marker for the diagnosis of thyroid cancer (TC) with recurrence or distant metastasis (DMs). However, some studies emerged with conflicting results. Therefore, we provide a meta-analysis to evaluate the diagnostic performance of CTC for detection of recurrence in patients of TC. METHODS: We searched PubMed, Web of Science, Cochrane library with the keywords "thyroid cancer" and "circulating tumor cells". Data extraction and risk of bias assessment were performed independently by two reviewers. The summary receiver operating characteristic curve (SROC) and other parameters were adopted to summarize the overall test performance. The sensitivity of CTCs in the detection of recurrent TC was reviewed. All analyses were performed by STATA 12.0 and Meta-disc software. RESULTS: For CTCs expressing epithelial cell adhesion molecule (EpCAM), seven studies were included in our meta-analysis. Pooled sensitivity, specificity, and diagnostic odds ratio were 0.71 (95% CI: 0.63-0.78), 0.89 (95% CI: 0.84-0.94), and 26.75 (95% CI: 9.11-78.53); 0.78 (95% CI: 0.65-0.89), 0.88 (95% CI: 0.76-0.96), and 40.01 (95% CI: 10.49-152.63) for CTCs expressing thyroid stimulating hormone receptor (TSHR). The area under the SROC for EpCAM and TSHR were both 0.91. CONCLUSION: CTC was a reliable marker for the diagnosis of TC patients with recurrence and DMs, and the sensitivity of CTCs expressing TSHR was higher than that of EpCAM. Additional research is warranted in order to establish uniformity in international guidelines, make up the drawbacks of conventional diagnostic methods and to prevent futile surgery.

Endoplasmic reticulum stress targeted therapy for breast cancer.

Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract.

Effect of statins use on risk and prognosis of breast cancer: a meta-analysis.

The findings regarding the association between statins use and breast cancer are inconsistent. Given the widely and long-term use of statins as first choice drug for dyslipidemia, we conducted this meta-analysis for better understanding the associations between statins use and the risk and prognosis of breast cancer. Articles regarding effect of statins use on risk, prognosis of breast cancer and published before January 2021 were searched in the following databases: Web of Science, PubMed, EMBASE, Medline and Google Scholar. Odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed to generate a pooled effect size and 95% CI. The meta-analysis showed no significant association between statins use and risk of breast cancer (OR/RR = 1.02; 95% CI, 0.97-1.08; I2 = 76.1%; P < 0.001). The meta-analysis showed that statins use was associated with lower breast cancer recurrence, all-cause mortality and disease-specific mortality (breast cancer recurrence: HR = 0.75; 95% CI, 0.67-0.84; I2 = 31.7%; P = 0.154; all-cause mortality: HR = 0.82; 95% CI, 0.77-0.89; I2 = 67.5%; P < 0.001; and disease-specific mortality: HR = 0.82; 95% CI, 0.72-0.93; I2 = 83.6%; P < 0.001). Overall, in this report we demonstrated that the use of statins can improve the prognosis of breast cancer patients including lower risks of breast cancer recurrence, all-cause and cancer-specific mortality, though statins therapy may not have an impact on reducing the risk of breast cancer.

Hyperthermia promotes exosome secretion by regulating Rab7b while increasing drug sensitivity in adriamycin-resistant breast cancer.

PURPOSE: To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. MATERIALS AND METHODS: We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. RESULTS: Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. CONCLUSIONS: Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Circulating metabolites serve as diagnostic biomarkers for HER2-positive breast cancer and have predictive value for trastuzumab therapy outcomes.

Human epidermal growth factor receptor 2 (HER2)-positive is a particularly aggressive type of the breast cancer. Trastuzumab-based therapy is a standard treatment for HER2-positive breast cancer, but some patients are resistance to the therapy. There are no known diagnostic biomarkers to improve the early diagnosis of HER2-positive breast cancer and the clinical utility of trastuzumab therapy. Using ultrahigh-performance liquid time of flight mass spectrometry (UPLC-TOF-MS)-based serum metabolomics and multivariate statistical analysis, we investigated and identified the circulating metabolites L-arginine and arachidonic acid were elevated in trastuzumab-responsive and trastuzumab-resistant HER2-positive breast cancer patients, and increased until reaching their peaks in trastuzumab-resistant HER2-positive breast cancer patients. Moreover, an equation for assessing the risk scores based on linear logistic regression models involving L-arginine and arachidonic acid was created, which was beneficial for revealing metabolic changes in HER2-positive breast cancer and enhancing current trastuzumab-based therapy. In summary, we develop serum-based metabolic biomarkers for diagnosis of HER2-positive breast cancers and predicts the therapeutic effects of trastuzumab therapy.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer: A pragmatic, multicenter, and prospective clinical trial in China.

Objective: This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive (ER+) early breast cancer in China. Methods: Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy. The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer, appearance of a second primary or contralateral breast cancer, or death due to any cause. Other endpoints included the proportion of patients experiencing each event, incidence rate per annum, relationships between human epidermal growth factor receptor 2 status and time to event, and relationship between disease history variables and time to event. Results: Overall, 558 patients were included in the full analysis set: 397 (71.1%) completed the study, 20 experienced an event, and 141 discontinued [47 owing to an adverse event (AE); 37 no longer willing to participate]. Median duration of treatment was 29.5 (range, 0.1-57.7) months. Median time to event was not reached. Event-free survival probability at 36 months was 91.4% (95% CI, 87.7%-95.1%). The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years (20/565). Multivariate analysis showed an association between tumor, lymph node, and metastasis stage at initial diagnosis and time to event [hazard ratio: 1.532 (95% CI, 1.129-2.080); P=0.006]. Most AEs were grade 1 or 2 in severity, with arthralgia (7.7%) being the most common treatment-related AE. Conclusions: This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+ breast cancer previously treated with adjuvant tamoxifen for 2-3 years. No new safety signals were identified in the Chinese population.

The role of long non-coding RNAs in drug resistance of cancer.

Long non-coding RNAs (lncRNAs), a class of long RNAs, are longer than 200 nucleotides in length but lack protein-coding capacity. LncRNAs, as critical genomic regulators, are involved in genomic imprinting regulation, histone modification and gene expression regulation as well as tumor initiation and progression. However, it is also found that lncRNAs are associated with drug resistance in several types of cancer. Drug resistance is an important reason for clinical chemotherapy failure, and the molecular mechanism of tumor resistance is complex, which is a process of multi-cause, multi-gene and multi-signal transduction pathway interaction. Then comprehending the mechanisms of chemoresistance will help find ways to control the tumor progression effectively. Therefore, in this review, we will construct lncRNAs /drug resistance interaction network and shed light on the role of lncRNAs in drug resistance.

MiR-145 in cancer therapy resistance and sensitivity: A comprehensive review.

MircoRNA (miRNA) are a group of small, non-coding, regulatory RNA with an average length of approximately 22 nucleotides, which mostly modulate gene expression post-transcriptionally through complementary binding to the 3'-untranslated region (3'-UTR) of multiple target genes. Emerging evidence has shown that miRNA are frequently dysregulated in a variety of human malignancies. Among them, microRNA-145 (miR-145) has been increasingly identified as a critical suppressor of carcinogenesis and therapeutic resistance. Resistance to tumor therapy is a challenge in cancer treatment due to the daunting range of resistance mechanisms. We reviewed the status quo of recent advancements in the knowledge of the functional role of miR-145 in therapeutic resistance and the tumor microenvironment. It may serve as an innovative biomarker for therapeutic response and cancer prognosis.

MiR-539 inhibits the malignant behavior of breast cancer cells by targeting SP1.

The aberrant expression of microRNAs (miRNAs) is involved in the initiation and progression of human cancers. In our study, we found that miR-539 was down-regulated in breast cancer tissues and cell lines. Decreased expression of miR-539 was significantly associated with lymph node metastasis in patients with breast cancer. Overexpression of miR-539 inhibited the proliferation and promoted apoptosis of breast cancer cells. Moreover, highly expressed miR-539 significantly suppressed the epithelial-mesenchymal transition (EMT) and sensitized cells to cisplatin treatment. Mechanistically, miR-539 was found to target the specificity protein 1 (SP1) and down-regulated the expression of SP1 in breast cancer cells. Knockdown of miR-539 consistently increased the expression of SP1. The expression of miR-539 in breast cancer tissues was negatively correlated with the expression of SP1. Restoration of SP1 significantly attenuated the inhibitory effect of miR-539 on the proliferation of breast cancer cells. Taken together, our results indicate that miR-539 has a tumor suppressive role in breast cancer via targeting SP1, suggesting miR-539 as a promising target for the diagnosis of breast cancer.

Current Status and Factors Influencing Surgical Options for Breast Cancer in China: A Nationwide Cross-Sectional Survey of 110 Hospitals.

BACKGROUND: There are limited nationwide data regarding breast cancer surgery in China. The Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons conducted a nationwide survey to examine the use of and barriers associated with surgical options among patients with breast cancer. METHODS: Surveys were sent via e-mail to the directors of 110 centers that performed at least 200 breast cancer operations in 2017. The electronic questionnaire contained 183 questions and covered six aspects, including demographic information about the hospitals and surgeons, surgical practice, and application of breast reconstruction. RESULTS: The selected hospitals were from 31 provinces or municipalities. The overall proportion of breast-conserving surgery (BCS) was 22%. Local gross domestic product was significantly related to the rate of BCS (p = .046). Sentinel lymph node biopsy was performed routinely in 76% of hospitals. Only 14.5% (16/110) of hospitals used the dual-tracer method, including radioisotopes. For patients with cN0 disease receiving BCS with one or two positive sentinel lymph nodes, 20% (22/110) of hospitals accepted omitting axillary lymph node dissection (ALND). For patients who underwent mastectomy, only 4% (4/110) of hospitals accepted omitting ALND. There was an obvious polarization trend in the proportion of oncoplastic breast-conserving surgery (OPS); 35/110 (32%) performed OPS in fewer than 10% of cases, whereas 36/110 (33%) performed OPS in more than 50% of cases. OPS was more likely to be performed in academic hospitals. Volume displacement was more commonly used than volume replacement (p < .001). Breast reconstruction was routinely performed in 96/110 (87%) of hospitals, 62% of which involved cooperation with the plastic surgery department. Factors influencing breast reconstruction after mastectomy included the establishment of a plastic surgery department, regional economy, and cooperation between the plastic and general surgery departments. Overall, the proportion of breast reconstruction procedures after mastectomy was 10.7%, with 70% being implant-based reconstruction, 17% autologous tissue reconstruction, and 13% a combination. Overall, 22% of the hospitals predominantly performed immediate breast reconstruction. For delayed reconstruction, two-stage implant-based breast reconstruction was the first choice for 46% of centers, whereas 20% of centers chose autologous reconstruction. Among the 96 centers that performed autologous-based reconstruction, 96% performed latissimus dorsi flap reconstruction, 65% performed transverse rectus abdominis musculocutaneous flap reconstruction, and 45% used deep inferior epigastric artery perforator flaps. CONCLUSION: The results are of great value for promoting the implementation of a consensus on diagnostic and treatment standards, development of guidelines for breast cancer, and training of breast specialists. IMPLICATIONS FOR PRACTICE: This study aimed to establish comprehensive baseline data on the status of current breast cancer treatment in China by presenting the statistics on clinical treatments and surgeries, the distribution of clinical stages, and the demographic characteristics of patients. This report is based on a survey conducted by the Chinese Anti-Cancer Association's Committee of Breast Cancer Society and the Chinese Society of Breast Surgeons, which examined the use of breast cancer surgical options in hospitals all over the country and the factors hindering the adoption of procedures and techniques. This study makes a significant contribution to the literature because there are limited nationwide data regarding breast cancer surgery in China.

RelB sustains endocrine resistant malignancy: an insight of noncanonical NF-κB pathway into breast Cancer progression.

BACKGROUND: The activation of the NF-κB pathway plays a crucial role in the progression of breast cancer (BCa) and also involved in endocrine therapy resistance. On the contrary to the canonical NF-κB pathway, the effect of the noncanonical NF-κB pathway in BCa progression remains elusive. METHODS: BCa tumor tissues and the corresponding cell lines were examined to determine the correlation between RelB and the aggressiveness of BCa. RelB was manipulated in BCa cells to examine whether RelB promotes cell proliferation and motility by quantitation of apoptosis, cell cycle, migration, and invasion. RNA-Seq was performed to identify the critical RelB-regulated genes involved in BCa metastasis. Particularly, RelB-regulated MMP1 transcription was verified using luciferase reporter and ChIP assay. Subsequently, the effect of RelB on BCa progression was further validated using BCa mice xenograft models. RESULTS: RelB uniquely expresses at a high level in aggressive BCa tissues, particularly in triple-negative breast cancer (TNBC). RelB promotes BCa cell proliferation through increasing G1/S transition and/or decreasing apoptosis by upregulation of Cyclin D1 and Bcl-2. Additionally, RelB enhances cell mobility by activating EMT. Importantly, RelB upregulates bone metastatic protein MMP1 expression through binding to an NF-κB enhancer element located at the 5'-flanking region. Accordingly, in vivo functional validation confirmed that RelB deficiency impairs tumor growth in nude mice and inhibits lung metastasis in SCID mice. Video abstract.